Acute coronary syndromes (ACS)
From Standard of Care
Thrombosis of a ruptured or eroded atherosclerotic plaque is the usual underlying precipitating factor for acute coronary syndrome.
Among the most common cardiac emergencies.
Risk of recurrent ischemic complications remains high despite early revascularization procedures and the dual antiplatelet therapy.
Estimated 2 million hospitalizations per year in the U.S.
Approximately 1.3 6 million hospitalizations each year, of which 0.8 1 million are for myocardial infarctions and the remainder for unstable angina.
Approximately 1,350,000 people have ACS with or without ST segment elevation annually.
Guidelines for the assessment of chest pain suggest that if the initial ECG is not diagnostic, but there is suspicion for acute coronary syndrome, serial ECGs at 15-30 minute intervals should be done to detect the development of ST-segment elevation or depression.
Approximately 2/3 of patients with myocardial infarction have non-ST elevation MI and the rest have ST elevation MI.
After an acute coronary artery disease event patients experience a high rate of serious complications including death, myocardial infarction and progressively recurring unstable angina requiring intervention.
Patients with high risk for ischemic complications during unstable angina/non-ST-segment elevation myocardial infarction include age greater than 75 years, anginal symptoms of greater than 20 minutes duration, acceleration of angina symptoms during the preceding 48 hours, findings of congestive heart failure, the presence of mitral regurgitation murmur, tachycardia, bradycardia, hypotension, the presence of transient ST-segment deviation of greater than 0.5 mm with angina at rest, the presence of a new bundle branch block on EKG, elevated cardiac biomarkers,and sustained ventricular tachycardia (Anderson JL).
Incidence of serious complications declines after 1 month, and then gradually diminishes so that after about 6 months, the incidence of coronary death and myocardial infarction is fairly constant for the next several years, reflecting a stabilization of the clinical coronary disease.
Recurrent ischemic events after PCI can be due recurrence at original treatment site, presence of untreated lesions, or progression in lesions.
Plaques with a high risk of disruption called vulnerable plaques.
Plaque stability varies with high risk or vulnerable plaques those with a large lipid core, thin fibrous caps, high density of macrophages and T lymphocytes, with a relative paucity of smooth muscle cells, increased expression of matrix metalloproteinases, outward remodeling, increased neovascularization and intraplaque hemorrhage.
Plaque rupture exposes thrombogenic sub endothelial components that lead to platelet deposition and activation.
Most retrospective studies show that atherosclerotic plaques responsible for ACS are angiographically mild (Ambrose JA et al, Glaser R et al)
Platelets that are activated express glycoprotein IIb/IIIa receptors to bind fibrin strands and stimulate platelet cross-linking.
Activated platelets release, local mediators, promoting further platelet accumulation, activation, vasoconstriction, thrombosis, and mitogenesis.
Two types of Andthrombi form after plaque rupture: a platelet rich clot (white clot) that forms in areas of high stress and only partly occludes the artery, or a fibrin rich clot (red clot) the result of an activated coagulation cascade and decreased flow in the artery.
Red clots are frequently superimposed on white clot and results in complete occlusion of the vessel.
Only white clots are found in unstable angina and non-STEMI, and STEMI associated with red clots (Sherman CT, DeWood MA).
Thrombotic coronary occlusion after rupture of a lipid-rich atheromatous plaque with only a thin layer of intima covering the thin cap fibroatheroma is the most common cause of MI and death from cardiac causes
Non critical stenosis (less than 50%) may be associated with abrupt progression to severe or total occlusion and account for as many as two-thirds of cases of ACS.
At least 80% of patients with ACS have multiple plaque ruptures distinct from the offending lesion (Rioufol G).
Autopsy studies have shown plaque rupture causes 75% of fatal myocardial infarctions, and superficial erosions accounts for the remaining 25%(Davies MJ).
Platelet thrombi can embolize distally and plug the microcirculation, which is associated with poor outcome.
Atherosclerotic plaques have heterogeneity, even among an individual.
Inflammation with macrophages increases the vulnerability of plaques by enlarging the lipid core, thins the plaque and increases risk of rupture.
CRP elevation correlates with number of plaque ruptures and may indicate the level of activity of macrophages.
Most patients have a series of vascular changes associated with coronary atherosclerosis resulting in the formation of one or more vulnerable plaques.
Non critical stenosis (less than 50%) may be associated with abrupt progression to severe or total occlusion and may account for as many as two-thirds of cases (Chen L).
Vulnerable plaques usually have high lipid content and macrophage content leading to mild to moderate luminal narrowing.
Plaque formation, primarily involves the intima of large medium sized arteries, which progresses throughout a person’s lifetime until manifesting as an acute ischemic event.
With endothelium damage monocytes, and other inflammatory cells, migrate to the subendothelium and bind to endothelial adhesion molecules and differentiate to become macrophages.
Macrophages digest oxidized LDL that also penetrate the arterial wall forming foam cells and formation of fatty streaks.
Activation of macrophages at the site release chemo attractants and cytokines that result in recruitment of additional macrophages and vascular smooth muscle cells at the site of the plaque.
Cytokines at the plaque site include monocytic chemo attractant protein 1, tumor necrosis factor alpha, and interleukins.
Vascular smooth muscle cells can synthesize extracellular matrix at the site of plaque.
Macrophages at the site of the plaque secrete matrix metalloproteinases which are enzymes that can digest extracellular matrix and lead to disruption of the plaque.
The smooth muscle to macrophage ration increases plaque vulnerability to rupture.
Rupture of the plaque can lead to this syndrome, but in 90% of cases it remains silent when it occurs.
Atherosclerosis lesion progression is variable, nonlinear and unpredictable (Virmani R).
In a prospective studt of patients with ACS undergoing 3 vessel coronary angiography and gray-scale and radiofrequency intravascular ultrasound after PCI: major adverse cardiovascular events occurred with follow-up with equal recurrence at the site of culprit lesions as to nonculprit lesions (Stone GW et al).
Coronary risk factors, including hypercholesterolemia, hypertension, diabetes and smoking influence the process.
Risk factors result in endothelial dysfunction and play a pivotal role in the initiation of atherosclerosis.
Dysfunctional endothelium has reduced bio availability of nitric oxide and has excessive production of endothelin-1, which impairs vascular hemostasis, increases adhesion molecules and increases thrombogenicity of blood via the secretion of locally active substances.
B-blockers treatment of choice.
Unstable angina, ST-segment elevation and non-Q-wave myocardial infarction.
ST elevation indicates that the culprit artery is completely occluded and that the patient will most likely develop a ST elevation myocardial infarction.
Absence of ST elevation in patients with unstable angina and non-Q wave myocardial infarction indicates that the culprit artery is only partially or intermittently occluded or that a rich collateral circulation exists.
With non ST elevation is diagnosed in a patient with acute ischemic symptoms and new EKG findings with ST-depression or T-wave inversion, or both, and such patients may have an elevation in cardiac enzymes.
Patients with non-ST elevation are recommended to have early evaluation with coronary artery catheterization.
Patients with non ST elevation and cardiac enzyme elevations are considered to have had an myocardial infarction while those without such enzymes have unstable angina.
Unstable angina, and non ST-elevation myocardial infarction are closely related processes with similar pathophysiology, and clinical presentation, but differed in their severity.
If biomarkers cannot be detected, hours after the initial onset of ischemic chest pain a patient is considered to have unstable angina.
Diagnosis of non-ST-elevation myocardial infarction can be made when the ischemia is sufficient to cause elevation of cardiac biomarkers such as troponins and creatine kinase.
In aspirin treated patients without ST elevation the use of short-term unfractionated heparin or low molecular heparin halves the risk of myocardial infarction or death.
Previously no convincing difference in efficacy or safety between low molecular heparin and unfractionated heparin, although recent systematic overview suggested enoxaparin is more effective than unfractionated heparin.
Nonocclusive intracoronary thrombi are present in 85% or more of patients with non-ST segment elevation suggesting that vascular occlusion that leads to myocardial infarction or sudden death results from repeated plaque fissures and mural thrombosis.
Vorapaxar use in acute coronary syndromes without ST-segment elevation and 82 standard dual antiplatelet therapy resulted in fewer myocardial infarctions (Becker RC etbal, Goto S et al).
In a multinational, double-blind, randomized trial comparing vorapaxar with placebo in 12,944 patients with acute coronary syndrome without ST-segment elevation: the addition of this agent to standard therapy did not reduce endpoints of myocardial infarction, stroke, recurrent ischemia, or urgent coronary revascularization, but did significantly increased the risk of major bleeding, including intracranial hemorrhage (Investigators in the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER).
Early strategy of angiography with triage to either percutaneous coronary intervention, coronary artery bypass or medical management results in reduced myocardial infarctions and deaths compared to those with conservative care.
Coronary CT angiography has a very high negative predictive value for the detection of coronary disease.
In a study of 1370 subjects with low to intermediate risk patients presenting with possible acute coronary syndromes a coronary CT angiography strategy was a safe process for the expedited discharge from the emergency department of many patients who would otherwise be admitted (Litt H et al).
Upstream use of platelet glycoprotein IIb/IIIa inhibitors prior to angiography reduces myocardial infarction and death rate at 30 days, at the expense of bleeding complications.
In patients with myocardial infarction and ST elevation, in which the infarcted artery is usually occluded an ongoing process of ischemia is present.
Because of the differences in the pathophysiology of unstable angina/NSTEMI compared to STEMI different therapeutic goals and treatment approaches are required.
In unstable angina/NSTEMI antithrombotic therapy is utilized to prevent further thrombosis, to allow endogenous fibrinolysis to dissolve the clot and to reduce the degree of coronary artery stenosis, while revascularization is used to increase blood flow and prevent reocclusion or recurrent ischemia.
In STEMI the artery is completely occluded and reperfusion with drugs or a catheter based reperfusion is the initial approach.
Symptoms of unstable angina/NSTEMI and STEMI are similar and require an EKG for differentiation.
The earlier primary percutaneous coronary intervention (PC I) can be performed, the lower the mortality.
In patients with acute coronary syndromes without ST segment elevations including unstable angina and myocardial infarction the involved artery is often patent , and there is usually no ongoing transmural ischemia and the patient often has a good response to medical management.
Stable angina is typically described as deep, poorly localized chest or on discomfort that is exacerbated by physical activity or emotional distress and relieved by rest, nitroglycerin, or both, while unstable angina is more severe, occurs at rest and usually best described as pain.
Acute coronary syndrome pain is located in the substernal region, with radiation of the pain or pressure to the neck, jaw, left shoulder and left arm.
Some patients present with discomfort other than chest pain, and may have dyspnea, nausea, vomiting, diaphoresis and unexplained fatigue, described as anginal equivalent.
Rarely ACS may present as syncope.
Sharp, stabbing or pleuritic pain, or pain reproducible by palpation or movement, or localized with the tip of a finger are usually not ischemic. The
In a randomized study of 3031 patients with acute coronary syndromes without ST elevation undergoing early intervention that is coronary angiography, less than 24 hours after randomization or delayed intervention with coronary angiography more than 36 hours after randomization; early intervention did not differ greatly from delayed intervention in preventing the primary outcome of death, myocardial infarction, or stroke at. six months (MEHTA): but it did reduce rate of composite secondary outcomes of death, myocardial infarction or refractory ischemia and was superior to delayed intervention in high risk patients.
While glycoprotein IIb/IIIa inhibitors are indicated with acute coronary artery syndromes who are undergoing an invasive procedure the optimal timing of initiating such therapy is unknown.
The American College of cardiology and the American Heart Association recommend that patients with high-risk features receive aspirin, and clopidogrel or a glycoprotein IIb/IIIA inhibitor before angiography.
In a study of 9492 patients with ST elevation assigned to eptifibatide 12 hours or more before angiography found its use increased risk of bleeding and need for blood transfusion (Guigliano).
Clopidogrel beneficial in patients without ST-segment elevation.
Aspirin given for greater than 30 days reduces secondary vascular events by 25-30% after acute coronary syndromes, but the rate of death and myocardial infarction remains high.
CURE trial 12,562 patients adding clopidogrel to aspirin decreased combined incidence of cardiovascular deaths, myocardial infarction, and strokes from 11.4 to 9.3 percent.
Adding clopidogrel to aspirin increases severe bleeding from 2.7 to 3.7% in the management of this process.
Proton pump inhibitors often utilized prophylactically with clopidogrel to reduce gastrointestinal bleeding risk.
Clopidogrel-protein pump inhibitors (PPIs) may decrease effects of clopidogrel on platelet aggregation inhibition.
Clopidogrel-protein pump inhibitors (PPIs)-when utilized with clopidogrel after hospital discharge for acute coronary artery syndrome associated with increased risk of adverse outcomes compared to the use of clopidogrel alone.
Death or myocardial infarction occurs in 9-11% of patients with non-ST segment elevations within 4-6 weeks after the onset of symptoms.
Heparin mainstay of treatment for these syndromes.
Only low-molecular weight heparin-enoxaprin, has been shown to reduce the risk of coronary events in patients with non-ST segment elevation acute coronary ischemia.
Stroke uncommon (1.3%) associated event but stroke increases 6-month mortality by four-fold.
Patients more likely to carry PlA2 variant of the GP IIIa receptor than controls.
Enoxaprin is comparable to unfractionated heparin in the treatment of high-risk patients with non-ST-segment elevation acute coronary syndrome.
Bleeding during anticoagulant and anti-platelet therapy associated with increased risk of death, myocardial infarction and stroke.
Invasive strategies involving coronary angiography and revascularization results in reduced incidence of myocardial infarction, severe angina and rehospitalization over a follow-up of 17 months.
Aspirin, clopidogrel and an antithrombotic agent, either unfractionated heparin or low molecular weight heparin are also recommended for patients in whom an invasive strategy is chosen.
Routine invasive strategies associated with a higher early mortality rate.
Serial measurements of BNP after presentation predicts risk of death or new CHF.
In unstable angina coronary artery bypass graft surgery does not improve rates of myocardial infarction or death compared to medical treatment alone, but does improve, temporarily, the frequency and severity of anginal episodes.
5% of patients with atypical syndrome present with abdominal pains.